US20030069432A1 - Novel process for preparing 4-substituted-1h-pyrrole-3-carboxylic acid ester - Google Patents
Novel process for preparing 4-substituted-1h-pyrrole-3-carboxylic acid ester Download PDFInfo
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- US20030069432A1 US20030069432A1 US10/204,579 US20457902A US2003069432A1 US 20030069432 A1 US20030069432 A1 US 20030069432A1 US 20457902 A US20457902 A US 20457902A US 2003069432 A1 US2003069432 A1 US 2003069432A1
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- Prior art keywords
- compound
- formula
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- pyrrole
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- 0 C.C.CC.[1*]/C=C/C([2*])=O.[1*]C1=CNC=C1C([2*])=O Chemical compound C.C.CC.[1*]/C=C/C([2*])=O.[1*]C1=CNC=C1C([2*])=O 0.000 description 9
- NWEWGZCIYPDWNK-IYPQHCRLSA-N C/C=C/C1=CC=CC2=CC=CC=C21.CC1=CNC=C1C1=CC=CC2=CC=CC=C21.CCC.O=CC1=CC=CC2=CC=CC=C12 Chemical compound C/C=C/C1=CC=CC2=CC=CC=C21.CC1=CNC=C1C1=CC=CC2=CC=CC=C21.CCC.O=CC1=CC=CC2=CC=CC=C12 NWEWGZCIYPDWNK-IYPQHCRLSA-N 0.000 description 2
- ZUMKXGRFMGELBI-UHFFFAOYSA-N C=NCN1N=NC2=CC=CC=C21 Chemical compound C=NCN1N=NC2=CC=CC=C21 ZUMKXGRFMGELBI-UHFFFAOYSA-N 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N CCC Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
Definitions
- the present invention relates to a novel process for preparing pyrrole ester compounds which are key intermediate in the preparation of farnesyl transferase inhibitors, an anti-cancer agent (see: Ko, J. S. et al., WO 9928315).
- Horner-Emmons reaction of aldehyde compounds provides the corresponding ⁇ , ⁇ -unsaturated esters, which without any separation and/or purification steps, are treated with toluenesulfonylmethylisocyanate (TosMIC: hereinafter referred to as ‘TosMIC’) in the presence of base to give pyrrole esters in one-pot fashion.
- TosMIC toluenesulfonylmethylisocyanate
- R 1 and R 2 independently of one another represent C 1 -C 4 -alkyl.
- BetMIC Kermostatrizky, A. R. et.al. Heterocycles, 1997, 44, 67.
- BetMIC Kerky, A. R. et.al. Heterocycles, 1997, 44, 67.
- R represents alkyl, allyl, or aryl
- E represents an electron-withdrawing group.
- the general synthesis of 3-substituted-4-pyrrole ester contains two discrete stages.
- the first stage is the preparation and purification of ⁇ , ⁇ -unsaturated compound and the second stage is the cyclization reaction of the purified ⁇ , ⁇ -unsaturated compound with TosMIC in the presence of base.
- the conventional method requires purification step after the preparation of ⁇ , ⁇ -unsaturated compound, it is inevitable to efflux the reaction solvent as waste unless it is recycled. To remove the efflux of waste solvent and increase the efficiency of the process, it is proposed to run the two reactions in the same solvent as one-pot fashion.
- the object of the present invention is to provide a process for preparing a desired pyrrole ester derivative represented by the following formula (1):
- R represents alkyl, allyl, or aryl
- R 1 represents C 1 -C 4 -alkyl, by reacting an aldehyde compound represented by the following formula (2):
- R and R 1 are defined as previously described, and subsequently by adding TosMIC and the same base as used in the previous step in an amount of 1 to 1.5 molar equivalent with respect to the compound of formula (2).
- the alkali metal alkoxide base in an amount of 1 to 1.5 molar equivalents with respect to the compound of formula (2). If the amount of base is deviated from the defined range, the reaction to prepare the unsaturated ester compound of formula (4) is not proceeded cleanly. As a result, the object of the present invention to react the unsaturated ester compound directly in the next step in the same reaction system without being separated cannot be achieved.
- alkali metal methoxide, -ethoxide, -t-butoxide, -t-pentoxide, etc. preferably sodium- or potassium-t-butoxide or -t-pentoxide can be used.
- the reaction is well proceeded by using the base in an amount of 1 to 1.5 molar equivalents, however, 1 to 1.3 molar equivalent thereof may be sufficient to exhaust the aldehyde compound.
- an excess base may cause hydrolysis in the subsequent separation step of layers, it is preferable to use the base in an amount of 1 to 1.3 molar equivalent in order to minimize such a hydrolysis reaction.
- any inert solvent which does not adversely affect to the reaction can be used in the process according to the present invention, but tetrahydrofuran, dimethoxyethane, toluene or mixtures thereof is preferably used.
- the organic layer was separated and stirred at room temperature, and the formed precipitate is filtered to give the desired compound of formula (1) in a pure state.
- the solvent is not always required to remove before carrying out the extraction. But, in case of tetrahydrofuran or dimethoxyethane is used as the reaction solvent, since they are well miscible with water, it is required to be removed by distillation. Therefore, the increase of yield can be expected if the solvent is removed in advance by distillation under reduced pressure before the extraction.
- the extracting solvent for this purpose, toluene or n-butyl acetate can be preferably used. Particularly, when sodium-t-pentoxide is used as the base, since this base is well soluble in the preferable extracting solvent toluene, the trouble to have to use an extracting solvent different from the reaction solvent may be saved.
- the reaction for preparing the compound of formula (4) is proceeded at temperature ranging from ⁇ 20 to 40° C., preferably 10 to 25° C. on a satisfactory level. Also, the process for producing the desired pyrrole ester derivative of formula (1) from the compound of formula (4) thus obtained is suitably carried out at temperature ranging from 0 to 40° C.
- TosMIC(36.9 g, 0.189 mol) and sodium-t-pentoxide(23.8 g, 0.216 mol) were added slowly in sequence maintaining the reaction temperature below 20° C. After the addition was completed, the reaction mixture was stirred for 3 to 6 hours at room temperature and 250 ml of distilled water was added. The resulting mixture was heated at about 70° C. and the organic layer was separated, washed once again with 250 ml of distilled water at the same temperature. The separated organic layer was subjected to azeotropic distillation to remove the residual moisture. Then, the concentrate was cooled to about 50° C. with slow stirring. After the crystal was precipitated, the reaction temperature was lowered to 0 to 5° C. and further stirred. The formed solid was filtered, washed twice with 30 ml of toluene and dried under nitrogen to give 29.6 g (HPLC Purity 96%PAR, Yield 62%) of the title compound as a white powder.
- the pyrrole ester compounds of formula (1) key intermediates for preparing farnesyl transferase inhibitors, an anti-cancer agent, can be prepared with a high purity and yield on an industrial scale.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrrole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
- The present invention relates to a novel process for preparing pyrrole ester compounds which are key intermediate in the preparation of farnesyl transferase inhibitors, an anti-cancer agent (see: Ko, J. S. et al., WO 9928315). Horner-Emmons reaction of aldehyde compounds provides the corresponding α,β-unsaturated esters, which without any separation and/or purification steps, are treated with toluenesulfonylmethylisocyanate (TosMIC: hereinafter referred to as ‘TosMIC’) in the presence of base to give pyrrole esters in one-pot fashion.
- The most typical method for the synthesis of 3-substituted-4-pyrrole ester compound is through the cyclization reaction of an isonitrile compound with an electrophilic α,β-unsaturated compound, as depicted in the following Reaction Scheme 1. As isonitrile part, TosMIC is the most well known reagent (van Leusen, A. M. et.al.Telahedron Lett. 1972, 52, 5337.).
- in which
- R1 and R2 independently of one another represent C1-C4-alkyl.
-
-
- in which
- R represents alkyl, allyl, or aryl, and
- E represents an electron-withdrawing group.
- As known in the previous arts, the general synthesis of 3-substituted-4-pyrrole ester contains two discrete stages. The first stage is the preparation and purification of α,β-unsaturated compound and the second stage is the cyclization reaction of the purified α,β-unsaturated compound with TosMIC in the presence of base. However, since the conventional method requires purification step after the preparation of α,β-unsaturated compound, it is inevitable to efflux the reaction solvent as waste unless it is recycled. To remove the efflux of waste solvent and increase the efficiency of the process, it is proposed to run the two reactions in the same solvent as one-pot fashion.
- Under the technical background as explained above, the present inventors have investigated extensively on the eradication of the waste solvent problem and the increase of the efficiency of the process for the purpose of mass production of pyrrole ester. As a result, we have come up with the present invention by combining the two stages of the pyrrole synthesis into one-pot/one stage process. Therefore, the pyrrole ester is obtained in high purity and in environmentally friendly manner.
-
- in which
- R represents alkyl, allyl, or aryl, and
-
-
-
- in which R and R1 are defined as previously described, and subsequently by adding TosMIC and the same base as used in the previous step in an amount of 1 to 1.5 molar equivalent with respect to the compound of formula (2).
-
- In the process of the present invention, it is very important to use the alkali metal alkoxide base in an amount of 1 to 1.5 molar equivalents with respect to the compound of formula (2). If the amount of base is deviated from the defined range, the reaction to prepare the unsaturated ester compound of formula (4) is not proceeded cleanly. As a result, the object of the present invention to react the unsaturated ester compound directly in the next step in the same reaction system without being separated cannot be achieved. As the base which can be used for such a purpose, alkali metal methoxide, -ethoxide, -t-butoxide, -t-pentoxide, etc., preferably sodium- or potassium-t-butoxide or -t-pentoxide can be used. Though the reaction is well proceeded by using the base in an amount of 1 to 1.5 molar equivalents, however, 1 to 1.3 molar equivalent thereof may be sufficient to exhaust the aldehyde compound. Further, an excess base may cause hydrolysis in the subsequent separation step of layers, it is preferable to use the base in an amount of 1 to 1.3 molar equivalent in order to minimize such a hydrolysis reaction.
- Any inert solvent which does not adversely affect to the reaction can be used in the process according to the present invention, but tetrahydrofuran, dimethoxyethane, toluene or mixtures thereof is preferably used.
- After the process for preparing the compound of formula (4) is completed, TosMIC and the same base as used in the previous reaction step were added and stirred until the α,β-unsaturated ester is completely removed to produce the pyrrole ester compound of formula (1). In this reaction, TosMIC is added in an amount of 1 to 1.3 molar equivalent with respect to the compound of formula (2) and the base is added in an amount fallen under the same range as mentioned in the previous step of preparing the compound of formula (4). Then, the reaction solution is quenched with water and extracted with a suitable extracting solvent which is not miscible with water at temperature of 40 to 90° C. (if a high yield is desired, 60 to 90° C. is preferable). The organic layer was separated and stirred at room temperature, and the formed precipitate is filtered to give the desired compound of formula (1) in a pure state. The solvent is not always required to remove before carrying out the extraction. But, in case of tetrahydrofuran or dimethoxyethane is used as the reaction solvent, since they are well miscible with water, it is required to be removed by distillation. Therefore, the increase of yield can be expected if the solvent is removed in advance by distillation under reduced pressure before the extraction. As the extracting solvent for this purpose, toluene or n-butyl acetate can be preferably used. Particularly, when sodium-t-pentoxide is used as the base, since this base is well soluble in the preferable extracting solvent toluene, the trouble to have to use an extracting solvent different from the reaction solvent may be saved.
- The reaction for preparing the compound of formula (4) is proceeded at temperature ranging from −20 to 40° C., preferably 10 to 25° C. on a satisfactory level. Also, the process for producing the desired pyrrole ester derivative of formula (1) from the compound of formula (4) thus obtained is suitably carried out at temperature ranging from 0 to 40° C.
- Contrary to the prior arts, after the unsaturated ester compound of formula (4) is produced, it directly reacts with TosMIC without any separation or purification, in the present invention to afford the pyrrole ester. Thus, reduction of the waste solvent and enhancement of the efficiency of the process is obvious and provides great advantage particularly when the process is applied on an industrial production.
- The present invention will be more specifically explained in the following examples. However, it should be understood that they are intended to illustrate the present invention but not in any manner to limit the scope of the present invention.
-
- 1-Naphthaldehyde(35 g, 0.224 mol) and triethylphosphonoacetate(50 g, 0.224 mol) were mixed under nitrogen atmosphere, 180 ml of dimethoxyethane(DME) was added, and the resulting mixture was cooled to 0° C. under a thorough stirring. To this solution was added slowly potassium-t-butoxide(30 g, 1.2 molar equivalent) while maintaining reaction temperature below 20° C. After confirming the complete removal of 1-naphthaldehyde by HPLC, TosMIC(52.5 g, 1.2 molar equivalent) and potassium-t-butoxide(32 g, 1.3 molar equivalent) were added slowly in sequence maintaining the reaction temperature below 20° C. After confirming the exhaustion of at α,β-unsaturated ester by HPLC, 70 ml of distilled water was added and DME was removed therefrom by distillation under reduced pressure. 200 ml of toluene was added to this concentrate. The mixture was warmed and extracted with 350 ml of distilled water. The separated organic layer was subjected to azeotropic distillation to remove the residual moisture. The concentrate was cooled with slow stirring to room temperature and the formed solid was filtered. The filter cake was washed twice with 30 ml of cold toluene, twice with 50 ml of distilled water, and dried to give 37 g (HPLC Purity 95.2%, Yield 61%) of the title compound as a white powder.
-
- m.p.(not calibrated) 164-165° C.
-
- 1-Naphthaldehyde(28 g, 0.18 mol) and triethylphosphonoacetate(40.35 g, 0.18 mol) were introduced into 500 mL round bottom flask and diluted with 180 ml of toluene. The reaction mixture was cooled to about 0 to 5° C. and sodium-t-pentoxide (23.8 g, 0.216 mol) was added slowly in order to maintain the reaction temperature below 20° C. After the addition was completed, the reaction mixture was stirred for 1 to 2 hours at room temperature and cooled again to 0 to 5° C. TosMIC(36.9 g, 0.189 mol) and sodium-t-pentoxide(23.8 g, 0.216 mol) were added slowly in sequence maintaining the reaction temperature below 20° C. After the addition was completed, the reaction mixture was stirred for 3 to 6 hours at room temperature and 250 ml of distilled water was added. The resulting mixture was heated at about 70° C. and the organic layer was separated, washed once again with 250 ml of distilled water at the same temperature. The separated organic layer was subjected to azeotropic distillation to remove the residual moisture. Then, the concentrate was cooled to about 50° C. with slow stirring. After the crystal was precipitated, the reaction temperature was lowered to 0 to 5° C. and further stirred. The formed solid was filtered, washed twice with 30 ml of toluene and dried under nitrogen to give 29.6 g (HPLC Purity 96%PAR, Yield 62%) of the title compound as a white powder.
- According to the process of the present invention, the pyrrole ester compounds of formula (1), key intermediates for preparing farnesyl transferase inhibitors, an anti-cancer agent, can be prepared with a high purity and yield on an industrial scale.
Claims (10)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR20000008452 | 2000-02-22 | ||
KR2000/8452 | 2000-02-22 | ||
PCT/KR2001/000201 WO2001062727A1 (en) | 2000-02-22 | 2001-02-12 | Novel process for preparing 4-substituted-1h-pyrrole-3-carboxylic acid ester |
Publications (2)
Publication Number | Publication Date |
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US20030069432A1 true US20030069432A1 (en) | 2003-04-10 |
US6559320B2 US6559320B2 (en) | 2003-05-06 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/204,579 Expired - Fee Related US6559320B2 (en) | 2000-02-22 | 2001-02-12 | Process for preparing 4-substituted 1H-pyrrole-3-carboxylic acid ester |
Country Status (7)
Country | Link |
---|---|
US (1) | US6559320B2 (en) |
EP (1) | EP1257534B1 (en) |
JP (1) | JP2003523997A (en) |
AT (1) | ATE256660T1 (en) |
AU (1) | AU3612501A (en) |
DE (1) | DE60101557D1 (en) |
WO (1) | WO2001062727A1 (en) |
-
2001
- 2001-02-12 US US10/204,579 patent/US6559320B2/en not_active Expired - Fee Related
- 2001-02-12 DE DE60101557T patent/DE60101557D1/en not_active Expired - Lifetime
- 2001-02-12 AU AU36125/01A patent/AU3612501A/en not_active Abandoned
- 2001-02-12 JP JP2001561735A patent/JP2003523997A/en active Pending
- 2001-02-12 EP EP01908380A patent/EP1257534B1/en not_active Expired - Lifetime
- 2001-02-12 WO PCT/KR2001/000201 patent/WO2001062727A1/en active IP Right Grant
- 2001-02-12 AT AT01908380T patent/ATE256660T1/en not_active IP Right Cessation
Also Published As
Publication number | Publication date |
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WO2001062727A1 (en) | 2001-08-30 |
DE60101557D1 (en) | 2004-01-29 |
JP2003523997A (en) | 2003-08-12 |
ATE256660T1 (en) | 2004-01-15 |
EP1257534A4 (en) | 2003-04-02 |
EP1257534B1 (en) | 2003-12-17 |
AU3612501A (en) | 2001-09-03 |
US6559320B2 (en) | 2003-05-06 |
EP1257534A1 (en) | 2002-11-20 |
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